Hippocampal synaptic function and learning and memory are vulnerable to alterations in protein O- GlcNAcylation, the O-linked attachment of ?-N-acetylglucosamine (GlcNAc) to serine/threonine (ser/thr) residues. O-GlcNAcylation is now recognized as a possible therapeutic target for cognitive dysfunction, particularly in the treatment of Alzheimer's disease (AD), where decreased O-GlcNAc may be permissive for pathological tau hyperphosphorylation. Systemic administration of the OGA inhibitor, thiamet-G, reversed the increase in tau phosphorylation and improved spatial learning and memory in transgenic AD mice. Obviously, determining how O-GlcNAcylation modulates neuronal and synaptic function under physiological and pathophysiological conditions is imperative to understanding its impact on learning and memory, and the risks and benefits of therapeutic intervention. Our lab has made significant contributions to this new area of research by showing that acute and selective increase in O-GlcNAcylation of AMPAR GluA2 subunits underlies expression of a novel form of LTD at CA3- CA1 synapses (O-GlcNAc LTD), as well as the dampening pathological hyperexcitability in seizure models. We also find that acute increases in O-GlcNAc interferes with some forms of hippocampus-dependent learning and memory. Because excitation/inhibition balance in memory circuits governs normal learning and memory, and GABAAR function and trafficking is modified by serine phosphorylation, we have used our expertise to investigate how rapid changes in O-GlcNAcylation occurring under physiological conditions modulates the efficacy of GABAergic inhibition. Importantly, because not all GABAergic interneurons express GluA2 subunits, O-GlcNAc LTD will only occur at glutamatergic synapses on a subset of interneurons, which will alter circuit dynamics when O-GlcNAcylation is high. In preliminary experiments, we found that acutely increasing protein O-GlcNAcylation decreases the amplitude and frequency of sIPSCs and the amplitude of mIPSCs recorded from CA1 pyramidal cells in rat hippocampal slices. In this exploratory proposal, we test the hypothesis that O- GlcNAcylation directly modulates the strength of synaptic inhibition via postsynaptic GABAARs and receptor internalization, and indirectly via expression of O-GlcNAc LTD at excitatory synapses onto specific interneurons possessing GluA2-containing AMPARs. The results of these exploratory studies will establish an entirely novel fundamental mechanism that directly and indirectly controls GABAergic inhibition, thereby providing a framework for future studies targeting O-GlcNAc in neurodegenerative diseases, such as Alzheimer's disease, and in neurodevelopmental disorders such as autism and Down syndrome, where imbalances in excitatory and inhibitory circuits underlie cognitive dysfunction. The results of these studies will make a huge advance in a field that is in its infancy.